Our goal is to improve the treatment and prevention of voice, speech and swallowing disorders. For this purpose, the pathogenesis and pathophysiology of neurogenic idiopathic disorders are being studied. Currently we are: 1) determining the role of sensory feedback in the production of symptoms in spasmodic dysphonia; 2) identifying gene mutations involved in familial laryngeal disorders; 3) determining the role of perceptual and learning abnormalities in idiopathic speech disorders; and, 4) developing effective new treatments for voice, speech and swallowing disorders. Significant advances have been made during the last year in all these areas. 1) Many patients report laryngitis, airway irritation, or laryngeal injury prior to the onset of spasmodic dysphonia (SD) and muscular tension dysphonia (MTD). To map out the laryngeal sensory pathways in the medulla we used the Becker strain of pseudorabies virus (PRV) in an animal model. Prior to a unilateral mucosal PRV injection, the opposing superior laryngeal nerve (SLN) and ipsilateral recurrent laryngeal nerve (RLN) were sectioned to isolate the ipsilateral SLN afferents for PRV transport to the brain stem for different survival times. In a control, the ipsilateral SLN and RLN were sectioned leaving the contralateral SLN intact. Blinded counts of PRV labeled neurons demonstrated count increases with increased survival times at several levels. Early labeling was mainly ipsilateral in particular subnuclei of the nucleus tractus solitarius (NTS), the area postrema, and the spinal trigeminal n. (5SP) and did not increase with survival. Later increases occurred bilaterally in the same regions at more rostral levels. The pathway of laryngeal afferent connections started from ipsilateral NTS subnuclei ascending to the contralateral NTS subnuclei and bilaterally to the lateral tegmental field and 5SP while descending later to neurons bilaterally in the caudal lateral reticular tract. Another animal model was developed this year to study changes in these brain stem pathways as a result of peripheral laryngeal inflammation. New techniques were successful for inducing acute localized laryngeal inflammation and quantifying the subsequent changes in neuronal activation and cytokine expression in the laryngeal sensori-motor pathways in the medulla. We are collaborating with another group to use in situ hybridization to confirm our initial findings. To examine the role of sensory feedback in symptom generation in spasmodic dysphonia (SD), laryngeal tremor and muscular tension dysphonia (MTD), a temporary bilateral chemical block of the superior laryngeal nerve was confirmed with air puff threshold testing. Blinded spectrographic measures of voice symptoms before and after block, demonstrated a significant group by treatment interaction. Voice breaks were reduced in SD and increased in vocal tremor while aperiodicity was reduced only in MTD. Afferent feedback played an important but different role in symptom generation in these disorders. Because MTD also improved following afferent block, this disorder may have a similar pathophysiology to SD. A double-blind study using a mucosal lidocaine drip is investigating the role of laryngeal sensation in symptom generation in these disorders. 2) A gene mutation responsible for a motor neuronopathy first affecting the larynx was found in collaboration with the Neurogenetics Branch, NINDS. A family with an automsomal dominant motor neuronopathy showed linkage to chromsome 2p13 with a maximum of score of 4.05. A single base-pair change in the p150 subunit of the transporter protein dynactin was present in all the affected members The phenotype was distinctive, with an abductor laryngeal paralysis causing an airway obstruction first followed by hand muscle atrophy. The particular role that this mutation has in the laryngeal motor neuron pathology is unclear and is under consideration for future research. 3) Studies of idiopathic familial speech disorders determined that distinctive perceptual and learning deficits occur in affected members in families with these disorders. By studying adults with persistent developmental speech disorder (PDSD), perception and learning impairments were examined independent of development. The PDSD adults were impaired in nonsense word learning task during recall, repetition, and perception. Significant differences also occurred in short-term memory. PDSD subjects were particularly impaired on non-English-like consonant combinations. Speech learning deficits in persons following developmental speech disorders may impact their language learning skills throughout life. In the same adults, a second study examined their perception of brief acoustic cues for speech perception involving discrimination of minimal pairs (?stay versus ?say). The PDSD adults had difficulties perceiving brief acoustic cues (formant transitions) in words and fast temporal cues in nonspeech stimuli. Therefore both perception, learning and memory deficits may play a role in this persistent speech production disorder. We have found autosomal dominant inheritance in a large kindred; a genome ?wide screen is being conducted in collaboration with the Section on System Biology of Communication Disorders, in the National Institute on Other Communication Disorders and Deafness. Adults who stutter, however, did not differ from controls on tests of speech motor learning skills, auditory perception for fine acoustic cues in speech, or the detection of brief temporal cues in nonspeech stimuli. This suggests that developmental stuttering does not involve the learning or perceptual skills affecting other developmental speech disorders. 4) We previously found that agents producing selective N-methyl-D-aspartate receptor blockade actively suppressed the occurrence of late R2 laryngeal adductor responses in the cat. One of these agents was dextromethorphan, a widely used antitussive agent. This year, we have initiated a double-blind acute study of the effects of dextromethorphan in contrast with lorazepam and a placebo to determine if there is a significant reduction in symptoms in SD. The pilot portion was completed with four subjects, and six subjects have completed all three phases of the study. This new line of translational research show promises in delivering the first oral therapy to control the symptoms of SD. Dysphagia, a significant health problem, usually stems from central nervous system injury, leaving peripheral muscles intact and functional but without appropriate control. Our aim is to initiate and augment movement for swallowing through functional electrical neuromuscular stimulation (FES) in an effort to prevent aspiration while eating. This year, we tested the hypothesis that muscle stimulation can be self-synchronized with volitional swallowing by normal adults. Following baseline recordings, volunteers repeatedly swallowed while triggering neuromuscular stimulation of an ipsilateral pair of muscles for laryngeal elevation over ten trials. By the fourth trial, the onset of contralateral muscle activation and self-stimulation were coincident; demonstrating that normal subjects could easily combine stimulation with swallowing. To determine if subjects would spontaneously modify their patterns to adapt to stimulation, we examined the effects of repeated stimulation trials on patterns of muscle activation for swallowing. No changes in muscle patterning occurred suggesting that muscle stimulation might be prescribed to augment a patient?s residual movement pattern to improve control and prevent aspiration. Both studies are now ongoing in persons with dysphagia. A patent application entitled, Methods and Devices for Intramuscular Stimulation of Upper Airway and Swallowing Muscle Groups,was filed this year based on this research.